Mutation in aging mice occurs in diverse cell types that proliferate postmutation

Abstract

SummaryTo determine the relationship between aging, cell proliferation and mutation in different cell types, hearts, brains and kidneys from G11 PLAP mice between 1 week and 24 months of age were examined. Mutant cells were Regardless of tissue and cell type, PLAP + cells occurred as singletons and in clusters, both of which increased in frequency with age. These data show that age-associated accumulation of mutant cells occurs in diverse cell types and is due to both new mutation and proliferation of mutant cells, even in cell types that tend to not proliferate.

Measuring Genome Instability in Aging – A Mini-Review

“…The advantage of the PLAP assay is that the mutant cells can be directly detected in situ using histochemical examination. Agedependent accumulation of somatic mutations was also observed in PLAP mice from 1 week to 24 months old in heart, kidney and brain [40] . An elevated mutation rate was observed in proliferating cells such as kidney epithelial cells, as well as in post-mitotic cells such as cardiomyocytes and neurons [40] .…”

“…Agedependent accumulation of somatic mutations was also observed in PLAP mice from 1 week to 24 months old in heart, kidney and brain [40] . An elevated mutation rate was observed in proliferating cells such as kidney epithelial cells, as well as in post-mitotic cells such as cardiomyocytes and neurons [40] . A somewhat similar mouse model, also capable of visualizing mutations directly in tissue, is the so-called PUN assay [41] .…”

Immune response to mutant neo-antigens

“…Thus, such a direct approach might have to wait until the technology that underlies deep sequencing has achieved a higher accuracy. Interestingly, Stringer et al 4 , 5 have elegantly demonstrated the existence of spontaneous mutations in non-transformed tissues from aged mice. To do so, they generated transgenic mice harboring an enzyme that is not actively synthesized owing to an upstream frame-shift mutation.…”

“…(3) The studies by Stringer et al 4 , 5 suggest new avenues to explore the other central tenet of our hypothesis, i.e., the elicitation of an immune response against neo-antigens expressed by non-malignant cells. In particular, mice could be engineered to carry immunogenic peptides that are expressed only upon mutational events that productively reverse an upstream frame-shift mutation.…”

Genetically-directed Sparse Neuronal Labeling in BAC Transgenic Mice through Mononucleotide Repeat Frameshift

“…In rare cases, microsatellite repeats exist in the coding regions of genes and may cause neurological disorders and cancer when frameshift occurs57. To date, there are a few mouse genetic studies that take advantage of mononucleotide repeat frameshift to study frameshift mutation rates in vivo 8910, or inducing mosaic Cre expression in intestinal cells1112. These studies did not reveal the potential of this approach for genetically directed sparse neuronal labeling, because the frameshift rate for G 11 repeat in the brain is about 10 −4 –10 −5 (Refs 8, 9, 10), which is much lower than the desirable sparse labeling frequency of about 1% neurons as in the classical Golgi method2.…”